Safety and efficacy of conversion from twice-daily tacrolimus (prograf) to once-daily prolonged-release tacrolimus (graceptor) in stable kidney transplant recipients.

BACKGROUND: Graceptor is a new modified-release once-daily formulation of tacrolimus with an efficacy and safety profile similar to twice-daily tacrolimus (Prograf), as identified by clinical trials, offering a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily Prograf to once-daily Graceptor in stable kidney transplant recipients. METHODS: We switched 33 Japanese patients who had undergone kidney transplantation ≥1 years before from twice-daily Prograf to once-daily Graceptor. The dose conversion ratio between Prograf and Graceptor was 1:1. We compared the following parameters: minimum tacrolimus concentration (C(min)); concentration dose per weight (CDW); serum creatinine (sCr); blood urea nitrogen (BUN); total cholesterol (TC); high-density lipoprotein cholesterol (HDL-C); uric acid (UA); fasting blood sugar (FBS). Time points for measurements were 1 month before study start and 1 and 2 months afterward. RESULTS: The mean age of the subjects in this study was 46.5 ± 13.1 years. Mean C(min) decreased from 4.55 ± 1.79 to 3.20 ± 1.22 ng/dL. The mean CDW also decreased, from 99.8 ± 69.5 to 75.0 ± 55.1 mg/dL/kg over the 2 months. There were no significant changes in sCR, BUN, UA, and FBS. Mean TC increased from 187.5 ± 51.4 to 194.3 ± 43.4 mg/dL, and mean HDL-C changed from 53.7 ± 12.0 to 56.1 ± 11 mg/dL. There were no episodes of rejection or infection. CONCLUSIONS: We conclude that switching from Prograf to Graceptor is safe and has the advantage of improving adherence. It could also have a beneficial effect in controlling glycemic levels and the adverse effects of tacrolimus. In many cases (25%-30%), the minimum concentration of tacrolimus decreased after changing tablets. With Graceptor, the ratio of area under trough level to area under the curve (AUC) is low compared with Prograf, resulting in low C(min) values of 1-2 ng/mL, and the AUC for Graceptor is very similar to that for Prograf.

Characterization of three forms of cytochrome P-450 isolated from liver microsomes of rats treated with 3-methylcholanthrene.

Three forms of cytochrome P-450, designated as P-450MC-I, P-450MC-II, and P-450MC-III, were isolated from liver microsomes of rats treated with 3-methylcholanthrene (MC) by using a high performance liquid chromatography (HPLC) technique. The major MC-inducible forms, P-450MC-I and P-450MC-II showed a single protein band on SDS-polyacrylamide gel electrophoresis giving a minimum molecular weight of 56,000 daltons. The oxidized absolute spectra of both cytochromes P-450 were of low spin type, having a Soret absorption peak at 417 nm. The CO-reduced difference spectra of these two cytochromes P-450 showed a peak at 447 nm. In a reconstituted system, both cytochromes P-450 exhibited similar high levels of catalytic activity for benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation. Anti-P-450MC-I IG and anti-P-450MC-II IG, which were produced against the corresponding cytochromes P-450, each formed a single continuous precipitin line with both P-450MC-I and P-450MC-II in Ouchterlony double diffusion tests. Amino acid sequence analysis revealed that the sequence of the NH2-terminal 18 amino acids of both enzymes was the same. Therefore, the major MC-inducible forms, P-450MC-I and P-450MC-II, were highly homologous, being indistinguishable from each other in terms of apparent molecular weight, spectral properties, substrate specificity and the NH2-terminal 18 amino acid residues, but clearly separable by HPLC. The characteristics of both P-450 forms appear to correspond to those of the previously reported P-450c (1). On the other hand, a minor form, P-450MC-III was different from P-450MC-I and P-450MC-II in chromatographic properties, apparent molecular weight, substrate specificity and immunochemical properties, and did not correspond to any P-450 species previously purified from MC-treated rat liver microsomes.